Nod2 is Required for Normal Alveolar Macrophage TNF-α. Secretion i.n Response to P. aeruginosa Challenge: a Crucial Innate Immune Receptor in Lung Infection
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Early detection of pathogens and subsequent regulation of the immune response are crucial to protect the lungs against harmful pathogens. These tasks are carried out by mechanisms of innate immunity, the body's initial non-specific defense against invading pathogens. A group of proteins involved in non-specific immunity are the Pattern Recognition Receptors (PRRs) such as the Toll-like Receptors (TLRs) and Nod-like Receptors (NLRs) that detect parts of invading pathogens called Pathogen Associated Molecular Patterns (PAMPs). Detection of the P AMPs by PRRs can cause production and secretion pro-inflammatory molecules such as Tumor Necrosis Factor (TNF-α.) or activation apoptotic signaling pathways via downstream clevage of inactive, proapoptotic caspases. Nucleotide-binding oligomerization domain containing 1 and 2 receptors (NodI and Nod2), members of the NLR family of proteins that detect PAMPs in the cytosol, have been documented as essential in the maintenance of intestinal microflora through activity in intestinal epithelial cells. They are also expressed in alveolar macrophages (AM) and alveolar epithelial cells (AEC), the major proinflammatory molecule secreting cells of the lung. Primary culture alveolar macrophages (AM) and alveolar epithelial cells (AEC) from Wild Type (WT) and NodI and/or Nod2 knockout mice were challenged with purified PRR stimulating molecules or Pseudomonas aeruginosa, an opportunistic bacteria known to cause serious infections in immunocompromised patients. AM and AEC TNF-α. secretion was measured by ELISA. Nod2 and double knockout AM showed a decrease in TNF-a. production compared to WT AM. AEC chemokine expression was elevated in the presence of TLR ligands co-stimulated with NodI or Nod2 ligands. The Data shows a crucial role for Nod2 in the production of pro-inflammatory master cytokine TNF-α, Implicating the receptor as a crucial mediator for initial detection and response to invasive P. aeruginosa.